Certain tetrahydrobenzindole derivatives



United States Patent ()fiice 3,232,953 i atented Feb. 1, M266 3,232,953CERTAlN TETRAHYDRUBENZHNDGLE DERHVATIVES Norbert Gruenteld, New York,N.Y., assignor to Geigy Chemical Corporation, Greenhnrgh, N.Y., acorpora= tion of Delaware No Drawing. Filed Dec. 31, 1962, Ser. No.248,223 8 Claims. (Cl. 2643-319) N-- OR t R1 FAQ R represents hydroxy,lower alkoxy, amino, lower monoalkylamino; and

R and R denote hydrogen, halogen (particularly, chlorine and bromine),lower alkyl, and lower alkoxy.

In this formula The term lower alkyl as used herein per se and asincluded in the term lower alkoxy means saturated monovalent aliphaticradicals of the general formula ,C H wherein m designates an integer ofless than six and is inclusive of both straight-chain and branchedchainradicals, such as, methyl, ethyl, n-propyl, iso-propyl, n-butyl, amyl,etc.

The compounds of this invention may be conveniently synthesized by areaction involving the cyclization of a 2 [(di(lower)alkylacylamidomalonate)methyl] ltetralone, yielding the Z-carboxy derivativeof 3,3a,4,5- tetrahydro-Ztl benflg]indoie which, if desired, can bereadily converted to the corresponding ester and amide.

More specifically, the subject compounds may be made by the followingsynthesis: acid addition salts of 3,3a,4,5- tetrahydro 2Hbenz[g]indole-Z-carboxylic acids are formed (1) by refluxing a2-[(di(lower)a1kyl acylamidomalonate)methyl]-l-tetralone with mineralacid, such as, hydrohalic (hydrochloric or hydrobromic) or sulfuricacid. The treatment with mineral acid causes hydrolysis, cyclization andmono-decarboxylation. These carboxy derivatives can be esterified (2) byany of the known esterification procedures, as for example, by refluxingwith a lower alkanol and sulfuric acid. The ester obtained, namely loweralkyl 3,3a,4,S-tetrahydro-ZI-l-benz [gjindole-Z-carboxylate, can beconverted (3) to corresponding amides, i.e.3,321,4,S-tetrahydro-ZH-benz[g]indole-Z-carboxamides by a well knownprocedure which involves aminolysis.

The synthesis of these compounds may be graphically illustrated by thefollowing equations:

(C O 0 Rs) 2 R14 orno HX Nnoon, R

t @BTTC 0 01111 R2 lilti c 0 on): 1 H R3011 R2 2 01-1 l [T|I-COOR3 R!- tRr- 1 i (3) N,-COOR; IT FC ONHR5 RP HQNR5 R1 R; R t

The symbols R and R in the above formulae have the significance ascribedto them hereinabove; X is a halide or sulfate anion, R stands for loweralkyl, R, is hydrogen, lower alkyl or aryl(lowcr) alkoxy and NHRrepresents amino and lower alkylamino,

The starting materials, namely 2-[=(di(lower)alkylacylamidomalonate)methyl]-l-tetralones can be synthesized from thecorresponding l-tetralones which are either commercially available orreadily obtainable in accordance with standard procedures. For example,6,7di-methoxy-1-tetralone yields via a Mannich reaction withparaformaldehyde and dimethylarnine hydrochloride,2-(dimethylarninomethyl)-6,7-dimethoxy-l-tetralone hydrochloride. Thisaffords the desired starting material, 2[(diethylacetamidornalonate)methyl] 6,7 dimethoxyl-tetralone, when condensed withdiethyl acetamidomalonate.

The present invention comprehends not only the abovedescribedderivatives of 3,3a,4,5-tetrahydro-2H-benz[g] indoles in their free baseform, but it also includes pharmaceutically acceptable non-toxic acidaddition salts which may be formed from said compounds in accordancewith conventional practice, by using appropriate inorganic and organicacids, such as hydrohalic acids, especially hydrochloric and hydrobromicacids, sulfuric, niethan-esultonic and phosphoric acids as well asacetic, lactic, succinic, malic, aconitic, phthalic and tartaric acids.

As mentioned above, the subject compounds possess valuablepharmacological properties; they have been found to possess adrenolytic,CNS depressant and, particularly, analgesic properties and can thereforebe characterized as tadrenolytic CNS depressant and analgetic agents.

Merely by way of illustration, the compound of Example 6,7,8-dimethoxy-3,3a,4,5-tetrahy-dro-ZH-benz[g] indole-Z-carboxamide,increased the painthreshold in the tailflick test by 37% at a dose of500 mg./kg., p.o.; at a .3 dose of 250 mg./kg., p.o., it reduced thenumber of stretches in the acetic acid analgesic test by 56%; and inHaffners test it decreased the number of bites at a dose of 500 mg/kg.p.o. by 23% of the mice and at a dose of 250 mg./kg. p.o. by 18% of themice.

These new compounds and the methods for their preparation may beexemplified more fully by the following illustrative examples; the scopeof the invention is however not limited thereto. The temperaturestherein are given in degrees centigrade.

EXAMPLE 1 3 ,3 a,4,5 -tetrahydr-2H -henz [g] indole-Z -carb0xyli 0 acidhydrochloride (0) 2 dimethylaminomethyl 1 tetralone hydrochloride.Amixture of l-tetralone (43.8 g., 0.3 mole), dimethylamine hydrochloride(27 g., 0.33 mole), paraformaldehyde (13.5 g., 0.45 mole), absoluteethanol (90 ml.) and hydrochloric acid (conc. 1.5 ml.) was heated underrefiux for two hours. Additional paraformaldehyde (9.0 g., 0.3 mole) wasadded and heating under reflux was continued for two additional hours.The hot reaction mixture was poured into boiling acetone (600 ml.). Thereaction product (44.7 g., M.P. 156-158 dec.) crystallized. This productwas recrystallized from ethanolacetone (1:5, 600 1111.), M1. 154-l56dec.; M.P. lit. 158-159".

(19) [(Diethylacetamidomalonate) methyl] 1 tetral0ne.Compound (a) (30.0g., 0.125 mole) was suspended in absolute ethanol (125 ml., dried bydistillation over sodium and diethyl succinate), and dimethyl sulfate(19.0 g., 0.15 mole) was added dropwise at room temperature. Thereaction mixture was stirred at room temperature for two hours and asolution resulted. Subsequent addition of diethyl acetamidomalonate(21.5 g., 0.10 mole) suspended in sodium ethoxide solution (prepared bydissolving 0.20 mole of sodium in 125 m1. of absolute ethanol) resultedin a slightly exothermic reaction. The mixture was stirred at roomtemperature for 18 hours. The reaction mixture was then added to ice(650 g.). The reaction product (32.7 g., M.P. 100-104) crystallized.Recrystallization from isopropanol (50 ml.) yielded the desired compound(25.7 g., M.P. 107-109). Further recrystallization gave pure material,M.P. 108- 110. Ultraviolet spectrum:

M on Maia.

EXAMPLE 2 Methyl 3,3a,4,5-letrahydro-ZH-benz [g] indole- Z-carboxylatehydrochloride The compound of Example 1 (12.6 g., 0.05 mole) wasdissolved in absolute methanol (125 ml.). Sulfuric acid (reagent grade,12.5 ml.) was added and the mixture was heated under reflux for threehours. Methanol was re moved by distillation under reduced pressure andthe residue was treated while cooling in an ice bath with saturatedsodium carbonate solution (to pH 9). The mixture was extracted withchloroform (3x150 ml.); the combined chloroform extract was washed withwater, dried over sodium sulfate and evaporated to dryness. The oilyresidue (11.9 g.) was dissolved in isopropanol (30 ml.) and ethanolicHCl (9.9 N, 6 ml.) was added. The hydrochloride salt crystallized (11.3g., Ml. 184 dec.) and was twice recrystallized from ethanol-isopropanol(1:5, 60 ml.) to give the desired compound (6.6 g., M.P. 184 dec.).Ultraviolet spectrum:

3,3a,4,5-letrahydro-ZH-henz [g] indole-Z-carboxamide Methyl 3,3a,4,5-tetrahydro 2H benz[g]-indole-2-car boxylate hydrochloride (26.6g., 0.1 mole) was dissolved in water ml.). The solution was neutralizedto pH 8-9 with saturated sodium carbonate solution and extracted withchloroform (3 X ml.). The chloroform extract was washed with water,dried over sodium sulfate and evaporated to dryness to yield methyl3,3a,4,5-tetrahydro-2H-benz[g]-indole-2-carboxylate (24.1 g.). A portion(6.5 g., 0.028 mole) was dissolved in methanol (100 ml.), the solutionwas saturated with ammonia and stored at room temperature in a pressurebottle for. one week. The solution was evaporated to dryness, theresidue was crystallized from isopropanol (ca. 50 ml.); yield, 4.6 g.,Ml. -158. Two recrystallizations from isopropanol yielded the desiredcompound (31 g., MP. 138-158"). Ultraviolet spectrum:

Analysis.-F0r C H N O: Calcd.: C, 72.87; H, 6.59; N, 13.08. Found: C,72.69; H, 6.71; N, 13.03.

Treatment of methyl 3,3a,4,5-tetrahydro-2I-I-benz[g]indole-2-carboxylate with methylamine in a similar manner gives thecorresponding 3,3a,4,5-tetrahydro-2H-benz [g] indole-Z- (N-methyl-carboxamide.

EXAMPLE 4 7,8-dimethoxy-3,3a,4,5-tetrahydro-ZH-benz[g]ind0le-Z-carboxylic acid hydrochloride (a)2-(dimelhylaminomelhyl)-6,7-dimeth0xy I-tetralone hydrochloride.Amixture of 6,7-dimethoxy-1-tetralone (10.3 g., 0.05 mole), (prepared inaccordance with R. D. Haworth and C. R. Mavin, J. Chem. Soc. 1932,1485), dimethylamine hydrochloride (4.5 g., 0.055 mole),paraformaldehyde (2.25 g., 0.075 mole), absolute ethanol (15 ml.) andhydrochloric acid (cone, 0.75 ml.) was heated under reflux for twohours. Additional paraformaldehyde (1.5 g., 0.05 mole) was added andheating under refiux was continued for two additional hours. The hotreaction mixture was poured into boiling acetone (50 ml.). The reactionproduct (13.1 g., M.P. 191192 dec.) crystallized. Two recrystallizationsfrom ethanol: acetone (1:2, ml.) gave the desired compound (6.8 g., M.P.191-192" dec.). Ultraviolet spectrum:

Riffs 231 mu (6,. 18,000); 274 mu (6, 12,000); 31 M (6, 8,500)

(b) 2-[ (diethyl acetamidomalolzate -methyl] 6,7dimethoxy 1tetral0zze.-2 dimethylaminomethyl 6,7- dimethoxy-tetralone hydrochloride(30 g., 0.1 mole) was suspended in absolute ethanol (15 0 ml. dried bydistillation over Na and diethyl succinate), and dimethyl sulfate (11.4ml., 0.12 mole) was added dropwise at room temperature. The reactionmixture was stirred at room temperature overnight. Subsequent additionof diethyl acetamidomalonate (17.2 g., 0.08 mole) suspended in sodiumethoxide solution (prepared by dissolving 0.16 mole of sodium in 100 ml.of absolute ethanol) resulted in a slightly exothermic reaction. Thereaction mixture was stirred at room temperature for 18, and was thenadded to ice (600 g.). The reaction product (29.4 g., MP. 126-128")crystallized. Two recrystallizations of a small batch (4.4 g.) fromisopropanol (15 ml.) gave 5 pure material (3.3 g., M.P. 128-130").spectrum:

mg? 229 m (6, 18,000); 270 my (6, 12,000); 308 m (6, 7,800)

7,8 dimethoxy 3,3a,4,5 tetrahydro 2H benz [g] ind0le-2carb0xylic acidhydr0chl0ride.-A suspension of the compound under (b) above (25 g.,0.057 mole) in 3 N hydrochloric acid (140 ml.) was heated under refluxfor 6 hours. The resulting solution was treated with charcoal, filteredand evaporated to dryness under reduced pressure. Acetone (150 ml.) wasadded to the resiude. The reaction product (14 g., M.P. 247-248 dec.)crystallized; a second crop weighed 5.1 g.; M.P. 236-237 dec. The crudeproduct was directly esterified.

7-bromo-1-tetralone, 7-methyl-1-tetralone and 6,7-dimethyl-l-tetralonegive, when subjected to the above described sequence of reactions,8-bromo-3,3a,4,5-tertahydro-2H-benz[ g] -indole-2-carboxylic acidhydrochloride, 8 methyl 3,3a,4,5 tetrahydro 2H benz[g]indole-2-carboxylic acid hydrochloride and 7,8-dimethyl-3,3a,4, tetrahydro 2Hbenz[g]indole 2 carboxylic acid hydrochloride, respectively.

EXAMPLE 5 M et/z yl 7,8 -d imcflz0xy-3 ,3a,4,5 -tetrahydr0-2H -benz [g]indole-Z-carboxylate W 308 m (6, 9,000 269 m (6, 14,000) 228 mAnalysis-4 01 C l-l NO Calcd.: C, 66.42; H, 6.62; N, 4.84. Found: C,66.51; H, 6.78; N, 4.88.

EXAMPLE 6 7,8-dimeth0xy-3,3a,4,5-tetrahydr0-2H-benz [g] ind Ole-2-carb0xamid e Methyl 7,8 dimethoxy 3,3a,4,5 tetrahydro 2H-benz[g]-indole-2-carboxylate (5.8 g., 0.02 mole) was suspended inmethanol (100 ml.). The suspension was saturated with ammonia and storedat room temperature in a pressure bottle for ten days. Methanol wasevaporated under reduced pressure and the residue (5.5 g.) was twicerecrystallized from methanol (200 ml.) to yield the desired compound(2.6 g., M.P. ZOE-210 dec.). Ultraviolet spectrum:

W 307 m (6, 10,400 268 m (6, 16,000); 226 my Analysis.For C H N OCalcd.: C, 65.67; H, 6.61; N, 10.21. Found: c, 65.82; H, 6.66; N, 10.06.

What is claimed is:

1. A compound selected from the group consisting of Ultraviolet NCORwherein R is a member selected from the group consisting of hydroxy,lower alkoxy, amino and lower mono-alkylamino; and

R and R are chosen from the group consisting of hydrogen, halogen, loweralkyl and lower alkoxy;

R and R are selected from the group consisting of hydrogen, halogen,lower alkyl and lower alkoxy and pharmaceutically acceptable acidaddition salts thereof;

wherein which comprises refluxing with mineral acid a compound of theformula ll (COORs)2 CHzC NHCOR4 V wherein R and R have the same meaningindicated above, R is lower alkyl and R is selected from the groupconsisting of hydrogen and lower alkyl.

References Cited by the Examiner Chemical Abstracts, vol. 33, pp. 587(1939).

Cram et 211.: Organic Chemistry, McGrawHill Book Company, Inc., NewYork, 1959, pages 25-26.

Rose et al.: Ed., The Condensed Chemical Dictionary, Reinhold PublishingCorp., New York, 1956, page 114.

Rydon et al.: J. Chem. Soc, pp. 2462-7 (1951).

NICHOLAS S. RIZZO, Primary Examiner.

IRVING MARCUS, Examiner.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF